LFB-R603, a Third-Generation Monoclonal Anti-CD20 Antibody Displays An Additive Antitumor Activity with Antileukemic Chemotherapeutic Agents in Mouse Xenograft Models

Abstract 1660

LFB-R603, a next generation anti-CD20 antibody currently in clinical development, is characterized by a specific glycosylation pattern containing a high percentage of non fucosylated antibodies molecules at the Fc site. This pattern of glycosylation increases the affinity of antibodies for human FcγRIIIa, resulting in an increased antibody dependent cell-mediated cytotoxicity (ADCC) by human FcγRIIIa-expressing effector cells. This antibody is currently in a phase I clinical trial in B-CLL patients and its use is planned to be expanded to other non-hodgkin's lymphomas (NHL) such as follicular and mantle cell lymphoma, as a single agent and in combination with chemotherapeutic agents.

The antitumor efficacy of LFB-R603 was studied in comparison with rituximab in combination with conventional chemotherapeutic agents in two models of NHL developed in immuno-deficient mice.

The RL cell line, derived from a patient with follicular lymphoma (FL), was xenografted in mice by subcutaneous injection. Tumor-bearing mice were treated intravenously during 4 weeks with the anti-CD20 antibodies used alone or in combination with suboptimal doses of cyclophosphamide 50 mg/kg or bendamustine 30 mg/kg.

LFB-R603 and rituximab displayed a dose-related antitumor activity. The tumor growth inhibition (TGI) was at day 30, 64% at 10 mg/kg, 84% at 30 mg/kg and 100% at 100 mg/kg for LFB-R603 compared with the untreated-group. For rituximab, the TGI was 84% at 30 mg/kg and 99% at 100 mg/kg. More interestingly, LFB-R603 at 100 mg/kg dose showed a significantly superior antitumor activity as a delay of 21 days in tumor growth was observed compared to rituximab (p=0.00001).

The combination of LFB-R603 or rituximab at 60 mg/kg with cyclophosphamide enhanced the effect observed with the antileukemic agent only and the additive effect was similar for the two antibodies as a delay of 13 days in tumor growth was observed for both combination-treated groups compared with the cyclophosphamide-treated group (p=0.00001). However, LFB-R603 displayed a significant higher antitumor activity against RL xenografts than rituximab when combined with bendamustine as a tumor growth delay of 7 days was observed between the two treated-groups (p=0.00001).

The NCEB cell line, derived from a patient with mantle cell lymphoma (MCL), was xenografted in mice by subcutaneous injection. In this model, LFB-R603 and rituximab injected once weekly up to 3 weeks displayed a dose-related TGI activity. A higher activity of LFB-R603 compared to rituximab was observed at all tested doses (3, 10, 30 and 60 mg/kg). TGI values at day 51 were 91% for LFB-R603 at 3 mg/kg versus 40% for rituximab, 88% for LFB-R603 at 10 mg/kg versus 57 % for rituximab and 100% for LFB-R603 at 30 and 60 mg/kg versus 66% for rituximab when compared with untreated-group.

In conclusion, LFB-R603 displayed a greater antitumor activity as compared to rituximab in two different non-clinical in vivo models of NHL, namely follicular and mantle cell lymphoma. Moreover, additive effects were obtained when LFB-R603 was combined with chemotherapeutic agents such as cyclophosphamide and bendamustine in the FL model.